Substituted-1-phthalazinamines as vr-1 antagonists

ABSTRACT

The present invention provides a compound of formula (I): in which Ar and R 1  are phenyl or a heteroaromatic group, R 2  is generally hydrogen, R 3  is hydrogen or alkyl and X, Y and Z are generally CH or N as VR-1 antagonists; or a pharmaceutically acceptable salt thereof; pharmaceutical compositions comprising it; its use in therapy; use of it to manufacture medicaments to treat pain or inflammation; and methods of treating pain or inflammation.

The present invention is concerned with N,6-diaryl or heteroarylsubstituted-1-phthalazinamines and analogues and derivatives thereof aswell as pharmaceutically acceptable salts and prodrugs thereof, whichare useful as therapeutic compounds, particularly in the treatment ofpain and other conditions ameliorated by the modulation of the functionof the vanilloid-1 receptor (VR1).

The pharmacologically active ingredient of chilli peppers has beenrecognised for some time to be the phenolic amide capsaicin. Theapplication of capsaicin to mucous membranes or when injectedintradermally, causes intense burning-like pain in humans. Thebeneficial effects of topical administration of capsaicin as ananalgesic is also well established. However, understanding of theunderlying molecular pharmacology mediating these responses to capsaicinhas been a more recent development.

The receptor for capsaicin, termed the vanilloid VR1 receptor, wascloned by Caterina and colleagues at UCSF in 1997 (Nature, 398:816,1997). VR1 receptors are cation channels that are found on sensorynerves that innervate the skin, viscera, peripheral tissues and spinalcord. Activation of VR1 elicits action potentials in sensory fibres thatultimately generate the sensation of pain. Importantly the VR1 receptoris activated not only by capsaicin but also by acidic pH and by noxiousheat stimuli. It is also sensitized by a number of inflammatorymediators and thus appears to be a polymodal integrator of painfulstimuli.

The prototypical VR1 antagonist is capsazepine (Walpole et al., J. Med.Chem., 37:1942, 1994) - VR1 IC₅₀ of 420 nM. A novel series ofsub-micromolar antagonists has also been reported recently (Lee et al,Bioorg. Med. Chem., 9:1713, 2001), but these reports provide no evidencefor in vivo efficacy. A much higher affinity antagonist has been derivedfrom the ‘ultra-potent’ agonist resiniferatoxin. Iodo-resiniferatoxin(Wahl et al., Mol. Pharmacol., 59:9, 2001) is a nanomolar antagonist ofVR1 but does not possess properties suitable for an oral pharmaceutical.This last is also true of the micromolar peptoid antagonists describedby Garcia-Martinez (Proc. Natl. Acad. Sci., USA, 99:2374, 2002). Mostrecently International (PCT) patent publication No. WO 02/08221 hasdescribed a novel series of VR1 antagonists, which are stated to showefficacy in a number of animal models. We herein describe another novelseries of VR1 modulators. These comprise predominantly VR1 antagonistsbut encompass VR1 partial antagonists and VR1 partial agonists. Suchcompounds have been shown to be efficacious in animal models of pain.Other VR1 antagonists are disclosed in WO 03/062209 (NeurogenCorporation).

The present invention provides compounds of formula (I):

wherein Ar is phenyl, a six-membered heteroaromatic group containingone, two or three nitrogen atoms or a five-membered heteroaromatic groupcontaining one, two, three or four heteroatoms chosen from oxygen,nitrogen and sulfur, at most one heteroatom being oxygen or sulfur, Arbeing optionally substituted with one, two or three groups independentlychosen from halogen, hydroxy, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₂₋₆alkenyloxy, C₂₋₆alkynyloxy, amino, haloC₁₋₆alkyl,haloC₂₋₆alkenyl, haloC₂₋₆alkynyl, hydroxyC₁₋₆alkyl, hydroxyC₂₋₆alkenyl,hydroxyC₂₋₆alkynyl, cyano, nitro, aminoC₁₋₆alkyl, aminoC₂₋₆alkenyl,aminoC₂₋₆alkynyl, C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆alkylthio,C₁₋₆alkoxycarbonyl, haloC₁₋₆alkoxy, haloC₂₋₆alkenyloxy,haloC₂₋₆alynyloxy, NR⁴R⁵, CONR⁴R⁵ or CO₂NR⁴R⁵ where each R⁴ and R⁵ isindependently hydrogen or C₁₋₆alkyl;

R¹ is phenyl, a six-membered heteroaromatic group containing one, two orthree nitrogen atoms or a five-membered heteroaromatic group containingone, two, three or four heteroatoms chosen from oxygen, nitrogen andsulfur, at most one heteroatom being oxygen or sulfur, Ar beingoptionally substituted with one, two or three groups independentlychosen from halogen, hydroxy, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₂₋₆alkenyloxy, C₂₋₆alkynyloxy, amino, haloC₁₋₆alkyl,haloC₂₋₆alkenyl, haloC₂₋₆alkynyl, hydroxyC₁₋₆alkyl, hydroxyC₂₋₆alkenyl,hydroxyC₂₋₆alkynyl, cyano, nitro, aminoC₁₋₆alkyl, aminoC₂₋₆alkenyl,aminoC₂₋₆alkynyl, C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆alkylthio,C₁₋₆alkoxycarbonyl, haloC₁₋₆alkoxy, haloC₂₋₆alkenyloxy,haloC₂₋₆alkynyloxy, NR⁴R⁵, CONR⁴R⁵ or CO₂NR⁴R⁵ where R⁴ and R⁵ are asdefined above;

R² is hydrogen, halogen, hydroxy, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkyl,C₂₋₆alkoxy, C₂₋₆alkenyloxy, C₂₋₆alkynyloxy, NR⁶R⁷ where R⁶ and R⁷ are,independently, hydrogen, C₁₋₆alkyl or C₁₋₆hydroxyalkyl, or R⁶ and R⁷,together with the nitrogen atom to which they are attached form a 4, 5or 6-membered stable heterocycle optionally containing an oxygen ringatom;

R³ is hydrogen or C₁₋₆alkyl;

each X, Y and Z is N or CR⁸ where R⁸ is hydrogen, halogen or C₁₋₆alkyl;

or a pharmaceutically acceptable salt thereof.

Ar is preferably unsubstituted or substituted by one or two groups. Armay be substituted by one group. Ar may be unsubstituted.

Any substituents on Ar are preferably independently chosen from halogen,hydroxy, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy, cyanoand C₁₋₆alkoxycarbonyl. Any substituents are more preferably fluorine,C₁₋₄alkyl, hydroxyC₁₋₄alkyl, haloC₁₋₄alkyl C₁₋₄alkoxy, cyano orC₁₋₄alkoxycarbonyl. Examples of substituents are trifluoromethyl,fluorine, methyl, methoxy, 2-hydroxyisopropyl, cyano, ethoxycarbonyl and2-fluoroisopropyl.

Ar is preferably phenyl or a 6-membered heteroaromatic ring. Ar isparticularly phenyl, pyridyl, imidazolyl, pyrazinyl, pyridazinyl orpyrimidinyl.

Particular embodiments of Ar include 3-trifluoromethylpyrid-2-yl,3-fluoropyrid-2-yl, 3-methylpyrid-2-yl, pyrid-2-yl,1-methylimidazol-2-yl, 3-methoxypyrid-2-yl,3-(2-hydroxyisopropyl)pyrid-2-yl, 5-trifluoromethylpyrid-2-yl,6-trifluoromethylpyrid-2-yl, 4-trifluoromethylpyrid-2-yl,4-methylpyridazin-3-yl, 5-methylpyrimidin-4-yl, 2-methylpyrazin-3-yl,4-trifluoromethylpyridazin-3-yl, 2-methoxyphenyl, 2-cyanophenyl,3,5-difluoropyrid-2-yl, 3-cyanopyrid-2-yl, 3-ethoxycarbonylpyrid-2-yland 3-(2-fluoroisopropyl)pyrid-2-yl.

It is preferred that Ar is pyridyl, and preferably monosubstituted.

It is preferred that Ar be monosubstituted at the ring position adjacentto the point of attachment of Ar to the rest of the molecule.

R¹ is preferably unsubstituted or substituted by halogen, C₁₋₆alkylhaloC₁₋₆alkyl, haloC₁₋₆alkoxy or C₁₋₆alkoxycarbonyl. The substituents onR¹ are more preferably fluorine, C₁₋₄alkyl, haloC₁₋₄alkyl,haloC₁₋₄alkoxy or C₁₋₄alkoxycarbonyl. Examples of substituents includetrifluoromethyl, tertiarybutyl, trifluoromethoxy, fluorine andethoxycarbonyl.

R¹ is preferably phenyl or pyridyl, particularly phenyl.

R¹ is preferably monosubstituted. The substituent is preferably para tothe point of attachment of R¹ to the rest of the molecule.

Particular embodiments of R¹ include 4-trifluoromethylphenyl,4-tert-butylphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl,4-ethoxycarbonylphenyl and 5-trifluoromethylpyrid-2-yl.

R² is preferably hydrogen, C₁₋₆alkoxy or NR⁶R⁷. R² is more preferablyhydrogen, C₁₋₄alkoxy, di(C₁₋₄alkyl)amino or morpholino. R² may behydrogen, methoxy, dimethylamino or morpholino. R² may be hydrogen.

R³ is preferably hydrogen.

R⁴ and R⁵ are preferably hydrogen or methyl, particularly hydrogen.

Preferably none or one of X, Y and Z is N and the others are CR⁸. R⁸ ispreferably hydrogen. Preferably Z is N and X and Y are CH.

Preferred subclasses of compounds are shown below:

in which R¹, R² and Ar are as defined above, including the preferreddefinitions.

Thus, in the compounds of formulae IA, IB, IC and ID:

Ar is phenyl or a six-membered heteroaromatic ring optionallysubstituted with one or two substituents independently chosen fromhalogen, hydroxy, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,C₁₋₆alkoxy, cyano and C₁₋₆alkylcarbonyl;

R¹ is phenyl or pyridyl, particularly phenyl, monosubstituted byhalogen, C₁₋₆alkyl, haloC₁₋₆alkyl, haloC₁₋₆alkoxy or C₁₋₆alkoxycarbonyl;and

R² is hydrogen, C₁₋₄alkoxy, di(C₁₋₄alkyl)amino or morpholino.

In one embodiment the compound of formula I is a free base.

Particular embodiments of the invention include:

-   N-(4-trifluoromethylphenyl)-6-(3-trifluoromethyl-2-pyridinyl)-1-phthalazinamine;-   6-(3-fluoro-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   N-(4-(tert-butylphenyl)-6-(3-trifluoromethyl-2-pyridinyl)-1-phthalazinamine;-   6-(3-methyl-2-pyridinyl)-N-(4-(trifluoromethylphenyl)-1-phthalazinamine;-   6-(3-methyl-2-pyridinyl)-N-(4-trifluoromethoxyphenyl)-1-phthalazinamine;-   6-(2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   N-(4-trifluoromethylphenyl)-2-(3-trifluoromethyl-2-pyridinyl)pyrido[2,3-d]pyridazin-5-amine;-   6-(1-methyl-1H-imidazol-2-yl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   4-methoxy-6-(3-methyl-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   7-(3-methyl-2-pyridinyl)-N-(4-trifluoromethylphenyl)pyrido[3,4-d]pyridazin-4-amine;-   4-dimethylamino-6-(3-methylpyridin-2-yl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   6-(3-methylpyridin-2-yl)-4-(morpholin-4-yl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   6-(3-methoxy-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   2-{2-[1-(4-trifluoromethylphenylamino)phthalazin-6-yl]pyridin-3-yl}propan-2-ol;-   N-(4-trifluoromethylphenyl)-6-(5-trifluoromethyl-2-pyridinyl)-1-phthalazinamine;-   N-(4-trifluoromethylphenyl)-6-(6-trifluoromethyl-2-pyridinyl)-1-phthalazinamine;-   N-(4-trifluoromethylphenyl)-6-(4-trifluoromethyl-2-pyridinyl)-1-phthalazinamine;-   6-(4-methyl-3-pyridazinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   6-(5-methyl-4-pyrimidinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   6-(3-methyl-2-pyrazinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   N-(4-trifluoromethylphenyl)-6-(4-trifluoromethyl-3-pyridazinyl)-1-phthalazinamine;-   N-(4-tert-butylphenyl)-6-(3-methyl-2-pyridinyl)-1-phthalazinamine    hydrochloride;-   N-(4-fluorophenyl)-6-(3-methyl-2-pyridinyl)-1-phthalazinamine;-   6-(2-methoxyphenyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   6-(2-cyanophenyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   3-(3-methylpyridin-2-yl)-N-(4-trifluoromethylphenyl)pyrido[2,3-d]pyridazin-8-amine;-   N-(4-ethoxycarbonylphenyl)-6-(3-methyl-2-pyridinyl)-1-phthalazinamine;-   6-(3,5-difluoro-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   6-(3-cyano-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   6-(3-ethoxycarbonyl-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   6-(3-(1-fluoro-1-methylethyl)-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;-   N-(4-trifluoromethylphenyl)-2-(3-chloro-2-pyridinyl)pyrido[2,3-d]pyridazin-5-amine;    and-   N-(5-trifluoromethyl-2-pyridinyl)-2-(3-trifluoromethyl-2-pyridinyl)pyrido[2,3-d]pyridazin-5-amine;-   or a pharmaceutically acceptable salt thereof.

As used herein, the term “alkyl” or “alkoxy” as a group or part of agroup means that the group is straight or branched. Examples of suitablealkyl groups include methyl ethyl n-propyl, i-propyl, n-butyl s-butyland t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy. “Alkylthio” shallbe construed in an analogous manner.

As used herein, the term “hydroxyC₁₋₆alkyl” means a C₁₋₆alkyl group inwhich one or more (in particular 1 to 3, and especially 1) hydrogenatoms have been replaced by hydroxy groups. Particularly preferred arehydroxyC₁₋₃alkyl groups, for example, CH₂OH, CH₂CH₂OH, CH(CH₃)OH orC(CH₃)₂OH, and most especially CH₂OH. “Aminoalkyl” shall be construed inan analogous manner.

As used herein, the terms “haloC₁₋₆alkyl” and “haloC₁₋₆alkoxy” means aC₁₋₆alkyl or C₁₋₆alkoxy group in which one or more (in particular, 1 to3) hydrogen atoms have been replaced by halogen atoms,especially-fluorine or chlorine atoms. Preferred are fluoroC₁₋₆alkyl andfluoroC₁₋₆alkoxy groups, in particular, fluoroC₁₋₃alkyl andfluoroC₁₋₃alkoxy groups, for example, CF₃, CH₂CH₂F, CH₂CHF₂, CH₂CF₃,OCF₃, OCH₂CH₂F, OCH₂CHF₂ or OCH₂CF₃, and most especially CF₃ and OCF₃.

As used herein, the terms “alkenyl” and “alkynyl” as a group or part ofa group means that the group is straight or branched. Examples ofsuitable alkenyl groups include vinyl and allyl. A suitable alkynylgroup is acetylene or propargyl.

When used herein, the term “halogen” means fluorine, chlorine, bromineand iodine. The most preferred halogens are fluorine and chlorine,especially fluorine.

When used herein, the term “C₁₋₆alkoxycarbonyl” denotes a C₁₋₆alkoxy ora haloC₁₋₆alkoxy radical attached via the oxygen atom thereof to acarbonyl (C═O) radical thus forming a C₁₋₆alkoxycarbonyl orhaloC₁₋₆alkoxycarbonyl radical. Suitable examples of such esterifiedcarboxy groups include, for example, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

Examples of 6-membered heterocycles are pyridine, pyrimidine, pyrazine,pyridazine and triazine.

Examples of 5-membered heterocycles are thiophene, furan, pyrrole,imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole,1,2,3-triazole, 1,2,4-triazole, oxadiazole, thiadiazole and tetrazole.

In a further aspect of the present invention, the compounds of formula(I) may be prepared in the form of a pharmaceutically acceptable salt,especially an acid addition salt.

For use in medicine, the salts of the compounds of formula (I) will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts which may, for example, be formed by mixinga solution of the compound according to the invention with a solution ofa pharmaceutically acceptable acid such as hydrochloric acid, fumaricacid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid,citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuricacid. Salts of amine groups may also comprise quaternary ammonium saltsin which the amino nitrogen atom carries a suitable organic group suchas an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include metal salts suchas alkali metal salts, e.g. sodium or potassium salts; and alkalineearth metal salts, e.g. calcium or magnesium salts. Particularlypreferred are the hydrochloride and besylate, particularly besylate,salts.

The salts may be formed by conventional means, such as by reacting thefree base form of the compound of formula (a) with one or moreequivalents of the appropriate acid in a solvent or medium in which thesalt is insoluble, or in a solvent such as water which is removed invacuo or by freeze drying or by exchanging the anions of an existingsalt for another anion on a suitable ion exchange resin.

The present invention also includes within its scope N-oxides of thecompounds of formula (I) above. In general, such N-oxides may be formedon any available nitrogen atom. The N-oxides may be formed byconventional means, such as reacting the compound of formula (I) withoxone in the presence of wet alumina.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of abiologically active substance (the “parent drug” or “parent molecule”)that requires transformation within the body in order to release theactive drug, and that has improved delivery properties over the parentdrug molecule. The transformation in vivo may be, for example, as theresult of some metabolic process, such as chemical or enzymatichydrolysis of a carboxylic, phosphoric or sulphate ester, or reductionor oxidation of a susceptible functionality.

The present invention includes within its scope solvates of thecompounds of formula (I) and salts thereof, for example, hydrates.

The compounds according to the invention may have one or more asymmetriccentres, and may accordingly exist both as enantiomers and asdiastereoisomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention. Furthermore, the compounds of formula (I) may also exist intautomeric forms and the invention includes within its scope bothmixtures and separate individual tautomers.

The present invention further provides pharmaceutical compositionscomprising one or more compounds of formula (I) in association with apharmaceutically acceptable carrier or excipient.

Preferably the compositions according to the invention are in unitdosage forms such as tablets, pills, capsules, powders, granules,sterile parenteral solutions or suspensions, metered aerosol or liquidsprays, drops, ampoules, auto-injector devices, suppositories, creams orgels; for oral parenteral intrathecal, intranasal, sublingual rectal ortopical administration, or for administration by inhalation orinsufflation. Oral compositions such as tablets, pills, capsules orwafers are particularly preferred. For preparing solid compositions suchas tablets, the principal active ingredient is mixed with apharmaceutical carrier, e.g. conventional tabletting ingredients such ascorn starch, lactose, sucrose, sorbitol talc, stearic acid, magnesiumstearate, dicalcium phosphate or gums, and other pharmaceuticaldiluents, e.g. water, to form a solid preformulation compositioncontaining a homogeneous mixture of a compound of the present invention,or a pharmaceutically acceptable salt thereof. When referring to thesepre-formulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid pre-formulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from 0.1 to about 500 mg of the activeingredient of the present invention. Favoured unit dosage forms containfrom 1 to 500 mg, for example 1, 5, 10, 25, 50, 100, 300 or 500 mg, ofthe active ingredient. The tablets or pills of the novel composition canbe coated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer that serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of painful conditions such as those listed below, asuitable dosage level is about 1.0 mg to 15 g per day, preferably about5.0 mg to 1 g per day, more preferably about 5 mg to 500 mg per day,especially 10 mg to 100 mg per day. The compounds may be administered ona regimen of 1 to 4 times per day.

It will be appreciated that the amount of a compound of formula (I)required for use in any treatment will vary not only with the particularcompounds or composition selected but also with the route ofadministration, the nature of the condition being treated, and the ageand condition of the patient, and will ultimately be at the discretionof the attendant physician.

The invention further provides a compound of formula (I) as definedabove, or a pharmaceutically acceptable salt thereof, for use intreatment of the human or animal body. Preferably, said treatment is fora condition which is susceptible to treatment by modulation (preferablyantagonism) of VR1 receptors.

The compounds of the present invention will be of use in the preventionor treatment of diseases and conditions in which pain and/orinflammation predominates, including chronic and acute pain conditions.Such conditions include rheumatoid arthritis; osteoarthritis;post-surgical pain; musculo-skeletal pain, particularly after trauma;spinal pain; myofascial pain syndromes; headache, including migraine,acute or chronic tension headache, cluster headache, temporomandibularpain, and maxillary sinus pain; ear pain; episiotomy pain; burns, andespecially primary hyperalgesia associated therewith; deep and visceralpain, such as heart pain, muscle pain, eye pain, orofacial pain, forexample, odontalgia, abdominal pain, gynaecological pain, for example,dysmenorrhoea, pain associated with cystitis and labour pain, chronicpelvic pain, chronic prostatitis and endometriosis; pain associated withnerve and root damage, such as pain associated with peripheral nervedisorders, for example, nerve entrapment and brachial plexus avulsions,amputation, peripheral neuropathies, tic douloureux, atypical facialpain, nerve root damage, and arachnoiditis; itching conditions includingpruritis, itch due to hemodialysis, and contact dermatitis; pain (aswell as broncho-constriction and inflammation) due to exposure (e.g. viaingestion, inhalation, or eye contact) of mucous membranes to capsaicinand related irritants such as tear gas, hot peppers or pepper spray;neuropathic pain conditions such as diabetic neuropathy,chemotherapy-induced neuropathy and post-herpetic neuralgia;“non-painful” neuropathies; complex regional pain syndromes; painassociated with carcinoma, often referred to as cancer pain; centralnervous system pain, such as pain due to spinal cord or brain stemdamage, low back pain, sciatica and ankylosing spondylitis; gout; scarpain; irritable bowel syndrome; inflammatory bowel disease; urinaryincontinence including bladder detrusor hyper-reflexia and bladderhypersensitivity; respiratory diseases including chronic obstructivepulmonary disease (COPD), chronic bronchitis, cystic fibrosis, asthmaand rhinitis, including allergic rhinitis such as seasonal and perennialrhinitis, and non-allergic rhinitis; autoimmune diseases; andimmunodeficiency disorders.

Thus, according to a further aspect, the present invention provides acompound of formula (I) for use in the manufacture of a medicament forthe treatment or prevention of physiological disorders that may beameliorated by modulating VR1 activity.

The present invention also provides a method for the treatment orprevention of physiological disorders that may be ameliorated bymodulating VR1 activity, which method comprises administration to apatient in need thereof of an effective amount of a compound of formula(I) or a composition comprising a compound of formula (I).

According to a further or alternative aspect, the present inventionprovides a compound of formula (I) for use in the manufacture of amedicament for the treatment or prevention of a disease or condition inwhich pain and/or inflammation predominates.

The present invention also provides a method for the treatment orprevention of a disease or condition in which pain and/or inflammationpredominates, which method comprises administration to a patient in needthereof of an effective amount of a compound of formula (I) or acomposition comprising a compound of formula (I).

According to a further aspect of the present invention, it may bedesirable to treat any of the aforementioned conditions with acombination of a compound according to the present invention and one ormore other pharmacologically active agents suitable for the treatment ofthe specific condition. The compound of formula (I) and the otherpharmacologically active agent(s) may be administered to a patientsimultaneously, sequentially or in combination. Thus, for example, forthe treatment or prevention of pain and/or inflammation, a compound ofthe present invention may be used in conjunction with other analgesics,such as acetaminophen (paracetamol), aspirin and other NSAIDs, includingselective cyclooxygenase-2 (COX-2) inhibitors, as well as opioidanalgesics, especially morphine, NR2B antagonists, bradykininantagonists, anti-migraine agents, anticonvulsants such as oxcarbazepineand carbamazepine, antidepressants (such as TCAs, SSRIs, SNRIs,substance P antagonists, etc.), spinal blocks, gabapentin, pregabalinand asthma treatments (such as

₂-adrenergic receptor agonists or leukotriene D₄antagonists (e.g.montelukast).

Specific anti-inflammatory agents include diclofenac, ibuprofen,indomethacin, nabumetone, ketoprofen, naproxen, piroxicam and sulindac,etodolac, meloxicam, rofecoxib, celecoxib, etoricoxib, parecoxib,valdecoxib and tilicoxib. Suitable opioid analgesics of use inconjunction with a compound of the present invention include morphine,codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone,levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol,fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxypheneand pentazocine; or a pharmaceutically acceptable salt thereof. Suitableanti-migraine agents of use in conjunction with a compound of thepresent invention include CGRP-antagonists, ergotamines or 5-HT₁agonists, especially sumatriptan, naratriptan, zolmatriptan orrizatriptan.

Therefore, in a further aspect of the present invention, there isprovided a pharmaceutical composition comprising a compound of thepresent invention and an analgesic, together with at least onepharmaceutically acceptable carrier or excipient.

In a further or alternative aspect of the present invention, there isprovided a product comprising a compound of the present invention and ananalgesic as a combined preparation for simultaneous, separate orsequential use in the treatment or prevention of a disease or conditionin which pain and/or inflammation predominates.

The compounds of formula 1 can be made by reacting a compound of formulaII with a compound of formula III:

in which Ar, R¹, R², R³, X, Y and Z are as defined above and one of Land L¹ is Cl or Sn(alkyl)₃, for example Sn(methyl)₃ or Sn(n-butyl)₃, andthe other is bromine or chlorine. When L or L¹ is Cl it can be initiallyconverted into a group B(OH)₂ under conditions suitable for a SuzukiCoupling Reaction (for review, see for instance A. Suzuki, Pure Appl.Chem., 1991, 63, 419-422), for example, in the presence of a palladiumcatalyst such as tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0),(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium ordichloro-(1,4-bis(diphenylphosphino)butane)palladium, in a suitablesolvent such as an ether, for example, dimethoxyethane or dioxane or anaromatic hydrocarbon, for example toluene, at an elevated temperatureand in the presence of a base such as sodium carbonate. Where L or L¹ isSn(alkyl)₃, the reaction is conveniently effected under conditionssuitable for a Stille Coupling Reaction (for review, see for instance J.K. Stille, Angew. Chem. Int. Ed., 1986, 25, 508-524), for example, inthe presence of a palladium catalyst such astetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride, in a suitable solventsuch as an ether, for example dioxane, or an aromatic hydrocarbon, forexample, toluene, at an elevated temperature, and in the presence ofcatalysts such as LiCl and CuI.

Compounds of formula II can be made by reacting a compound of formula IVwith a compound of formula HNR¹R³:

in which L is Br and X, Y, Z, R¹, R² and R³ are as defined above. Thereaction is generally carried out in a solvent such as dioxane in thepresence of an acid such as hydrochloric acid for about 30 to 60 minutesat about reflux.

Compounds of formula I can also be made by reacting a compound offormula V with a compound of formula HNR¹R³:

in which Ar, X, Y, Z, R¹, R² and R³ are as defined under similarconditions to the preceding reaction.

The compound of formula V can be made by reacting the fusedpyridazin-5(6H)-one precursor with phosphorus oxychloride at aboutreflux or 100° C. for about one to five hours.

This compound can be made by reacting a compound of formula VI:

in which Ar, R², X, Y and Z are as defined above, by the free radicaladdition of bromine using for example, N-bromosuccinimide and AIBN orbenzoyl peroxide in a non-protic solvent such as carbon tetrachloride atabout reflux in the presence of light for about 10 to 48 hours, followedby treating with hydrazine hydrate in a solvent such as ethanol at aboutreflux for about 18 hours.

Compounds of formula VI in which R² is H, Z is N and X and Y are CH, canbe made by reacting a compound of formula ArCN in which Ar is as definedabove with methylmagnesium iodide generally in a solvent such astetrahydrofuran at about room temperature for about one hour under aninert atmosphere, to produce a compound of formula ArC(O)CH₃. Thiscompound is reacted successively with dimethylformamide dimethylacetalgenerally in a microwave at about 160° C. for about 5 minutes and thenwith ethyl 3-aminocrotonate in a solvent such as glacial acetic acid atabout reflux for about six hours.

Compounds of formula IV in which R² is chlorine can be made by reactinga compound of formula VII:

in which L is bromine and X, Y and Z are as defined above with hydrazinehydrate generally in the presence of acetic acid at about 80° C. forseveral hours followed by reaction with one equivalent of phosphorusoxychloride generally in the presence of a base such as diisopropylaminefor about three hours at about reflux.

Compounds of formula II in which R² is C₁₋₆alkoxy can be made byreacting a compound of formula II in which R² is chlorine withsodiumC₁₋₆alkoxide in the corresponding alcohol at about reflux forabout five hours. Compounds of formula II in which R² is NR⁶R⁷, where R⁶and R⁷ are as defined above, can be made by reacting the compound offormula I in which R² is chlorine with a compound of formula HNR⁶R⁷generally in a solvent such as ethanol at about 100° C. for about 24hours.

Compounds of formula V in which R² is hydrogen, Y is N and X and Z areCR⁸ can be made by reacting a compound of formula VIII:

successively with a strong base, such as 2,2,6,6-tetramethylpiperidinemixed with n-butyllithium generally at a temperature of about −78° C. ina solvent such as tetrahydrofuran for about 90 minutes, then withdimethylformamide generally at about room temperature for several hours,then with hydrazine generally also in a solvent such as tetrahydrofuranfollowed by heating to reflux in the presence of a base such aspotassium acetate. Addition of the Ar group to the resulting bromopyridopyridazinone can occur via a Stille coupling as described above. Theresulting compound is converted into the compound of formula V usingphosphorus oxychloride as described above.

Compounds of formula I can be converted to other compounds of formula Iby standard methods.

Where the synthesis of intermediates and starting materials is notdescribed these compounds are commercially available or can be made fromcommercially available compounds by standard methods.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples serve to illustrate the preparation of compoundsof the present invention.

INTERMEDIATES Intermediate I Preparation of 6-bromo-1-chlorophthalazine

Described in WO-A-0281474.

Intermediate II 6-Bromo-N-(4-trifluoromethylphenyl)-1-phthalazinamine

To Intermediate I (2 g; 8.21 mmol) and 4-aminobenzotrifluoride (1.32 g1.024 mL; 8.21 mmol) in 1,4-dioxane (20 mL) was added 1 drop of conc.HCl. The reaction mixture was heated at reflux for 1 h. After cooling toroom temperature the insoluble material was collected by filtration,washed with 1,4-dioxane and dried. The solid was dissolved in ethylacetate and washed with saturated sodium carbonate. The ethyl acetateextracts were combined, washed with brine, dried over magnesiumsulphate, filtered and evaporated under reduced pressure to give asolid. The solid was rinsed with ethanol, the insoluble material wascollected by filtration and dried at 60° C. under vacuum to give 1.1 gof product. ¹H NMR (400 MHz) DMSO-d⁶ δ: 7.72 (2H, d, J 8.6), 8.18-8.23(3H, mn), 8.39 (¹H, d, J 2.0), 8.58 (1H, d, J 9.0), 9.20 (1H, s), 9.61(1H, s).

Similarly prepared were:

Intermediate III 6-Bromo-N-(4-trifluoromethoxyphenyl)-1-phthalazinamine

¹H NMR (400 MHz) DMSO-d⁶ δ: 7.38 (2 H, d, J 8.2), 8.02 (2 H, dd, J 2.0and 8.2), 8.21 (1 H, dd, J 1.8 and 8.8), 8.36 (1 H, d, J 1.6), 8.55 (1H, d, J 9.0), 9.13 (1 H, s), 9.39-9.60 (1 H, m); MS (ES M+1) 384/386.

Intermediate IV 6-Bromo-N-(4-tert-butylphenyl)-1-phthalazinamine

¹H NMR (400 MHz) DMSO-d⁶ δ: 1.31 (9 H, s), 7.38 (2 H, d, J 8.6), 7.79 (2H, d, J 7.8), 8.16 (1 H, dd, J 1.6 and 9.0), 8.31 (1 H, d, J 1.6), 8.54(1 H, d, J 9.0), 9.07 (1 H, s), 9.20 (1 H, s); MS (ES M+1) 356/358.

Intermediate V 6-Bromo-N-(4-ethoxycarbonylphenyl)-1-phthalazinamine

¹H NMR (400 MHz) DMSO-d⁶ δ: 1.33 (3H, t, J 7.0 Hz), 4.32 (2H, q, J 7.0Hz), 7.97 (2H, d, J 9.0 Hz), 8.12 (2H, d, J 9.0 Hz), 8.23 (1H, dd, J 2.0and 9.0 Hz), 8.39 (1H, d, J 2.0 Hz), 8.59 (1H, d, J 9.0 Hz), 9.21 (1H,s), 9.62 (1H, s).

Intermediate VI 6-Bromo- 1,4-dichlorophthalazine

5-Bromo-1,3-isobenzofurandione (14.8 g, 65.4 mmol) was suspended inacetic acid (150 mL), and treated with hydrazine hydrate at (10 mL) at80° C. overnight. The mixture was cooled, filtered, and the residue waswashed with methanol. The residue was triturated with 4M NaOH (ca. 250mL), and filtered. The pale yellow filtrate was acidified with conc. HCland filtered. The residue was azeotroped with toluene (×4), andsuspended in POCl₃ (75 mL). N,N-diisopropylethylamine (10 mL) was slowlyadded and the mixture was heated to reflux for 3 h and then concentratedunder reduced pressure, suspended in chloroform and filtered. Thefiltrate was poured onto ice, and the organic phase was washed withsodium bicarbonate solution, followed by brine. The organic phase wasdried (sodium sulfate) and filtered through a pad of silica, elutingwith chloroform, which after evaporation gave an off-white solid (6.5 g,36%). ¹H NMR (400 MHz) CDCl₃ δ: 8.14-8.20 (2H, m), 8.48 (1H, d, J 0.4);MS (ES M+1) 279.

Intermediate VII6-Bromo-4-chloro-N-(4-trifluoromethylphenyl)-1-phthalazinaminehydrochloride

Intermediate VI (3.29 g, 11.8 mmol) and 4-aminobenzotrifluoride (1.91 g,11.84 mmol) were suspended in ethanol and heated to reflux for 3 h. Themixture was filtered to give a pale-yellow solid (3.0 g); MS (ES M+1)404.

Intermediate VIII6-Bromo-4-methoxy-N-(4-trifluoromethylphenyl)-1-phthalazinamine

Intermediate VII (1.8 g, 3.96 mmol) and sodium methoxide (2.14 g, 39.6mmol) were suspended in dry methanol (15 mL), and heated to reflux for 5h. The mixture concentrated under reduced pressure and the residue waspartitioned between EtOAc/ammonium chloride, and the aqueous phase wasextracted with EtOAc (×2). The combined organic phases were washed(brine), dried (sodium sulfate) and concentrated to give a pale yellowsolid, which was recrystallized from DCM to give a white solid (175 mg,46%). ¹H NMR (400 MHz) DMSO-d⁶ δ: 4.14 (3H, s), 7.67 (2H, d, J 8.8),8.10 (2H, d, J 8.8), 8.22-8.28 (2H, m), 8.51 (1H, d, J 8.4), 9.38 (1H,s); MS (ES M+1) 398/400.

Intermediate IX6-Bromo-4-dimethylamino-N-(4-trifluoromethylphenyl)-1-phthalazinamine

Intermediate VII (107 mg, 0.24 mmol) was treated with dimethylamine (30%in ethanol, 3 mL) in a sealed tube at 100° C. for 24 h. The mixture wasconcentrated under reduced pressure, and the resulting residue waspartitioned between DCM/sodium bicarbonate solution. The aqueous phasewas extracted with DCM, and the combined organic phases were dried(sodium sulfate) and concentrated to give a yellow oil (87 mg) and usedin the coupling step without further purification. MS (ES M+1) 411/413.

Intermediate X6-Bromo-4-(morpholin-4-yl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

Intermediate VII (100 mg, 0.23 mmol) was suspended in ethanol (2 mL) andtreated with morpholine (0.099 mL, 1.14 mmol) in a sealed tube at 100°C. for 24 h. The resulting mixture was concentrated under reducedpressure, and the resulting residue was partitioned between DCM/sodiumbicarbonate solution. The aqueous phase was extracted with DCM, and thecombined organic phases were dried (sodium sulfate) and concentrated togive a yellow oil, which was used without further purification. MS (ESM+1) 453/455.

Intermediate XI 7-Bromo-3H-pyrido[3,4-d]pyridazin-4-one

2,2,6,6-Tetramethylpiperidine (9.58 mL, 56.4 mmol) was dissolved in dryTHF (100 ml), and cooled to 0° C., whilst n-butyllithium (1.6M inhexanes, 35.2 mL, 56.43 mmol) was added over 15 min. The resultingsolution was cooled to −78° C., and 6-bromonicotinic acid (3.8 g, 18.8mmol.) was added as a solid in four equal portions, with stirring over10 min. Stirring was continued at this temperature for 1.5 h, and theresulting deep-red solution was treated with dry DMF (10 mL) and allowedto warm to room temperature overnight. The mixture was poured onto water(200 mL) and acidified with 1M HCl, and the aqueous phase was extractedwith EtOAc (×4). The combined organic phases were washed (brine), dried(sodium sulfate) and concentrated to give a yellow oil, which wasdissolved in THF (25 mL) and treated with hydrazine (1M in THF, 19 mL).The precipitate was filtered, and dissolved in ethanol (50 mL) andheated to reflux in the presence of potassium acetate (5 g). The mixturewas concentrated under reduced pressure and the brown oily solid wastriturated with diethyl ether and the ethereal solution was subjected toflash chromatography (50% ethyl acetate/isohexane) to give a white solid(0.5 g, 12%). ¹H NMR (400 MHz) DMSO-d⁶ δ: 8.21 (1H, s), 8.36 (1H, s),9.20 (1H, s), 13.09, (1H, s). MS (ES M+1) 226/228.

Intermediate XII7-(3-Methylpyridin-2-yl)-3H-pyrido[3,4-d]pyridazin-4-one

Intermediate XI (104 mg, 0.46 mmol), anhydrous lithium chloride (59 mg,1.38 mmol), 3-methyl-2-tributylstannylpyridine (264 mg, 0.69 mmol), CuI(8.8 mg, 0.05 mmol) and Pd(PPh₃)₄ (26.6, 0.02 mmol) were suspended indioxane (4 mL) and irradiated with microwave radiation at 160° C. for 15min. The mixture was filtered, washing the residue with EtOAc. Theresidue was triturated with hot methanol filtered and the filtrate wasconcentrated to give a white solid (83 mg, 76%). ¹H NMR (360 MHz)DMSO-d⁶ δ: 2.56 (3H, s), 6.68 (1H, br), 7.06 (1H, d, J 6.3 Hz), 7.31(1H, br), 7.62-7.90 (2H, br m), 8.82 (1H, br). MS (ES M+1) 239.

Intermediate XIII6-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

Intermediate II (1.5 g; 4.07 mmol), bis(pinacolato)diboron (1.14 g; 4.48mmol), potassium acetate (0.80 g; 8.15 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.15 g;0.20 mmol) in 1,4-dioxane (50 mL) were heated at 100° C. for 18 h. Thesolvent was evaporated under reduced pressure and the residuepartitioned between ethyl acetate and water. The ethyl acetate extractswere combined, washed with brine, dried over magnesium sulphate,filtered through Hyflo and evaporated under reduced pressure to give asolid. The solid was tritiated with hexane and collected by filtrationand dried to give 1.8 g of the title compound. ¹H NMR (360 MHz) DMSO-d⁶δ: 1.37 (12 H, s), 7.71 (2H, d, J 8.6), 8.22 (3H, m), 8.43 (1H, s), 8.62(1H, d, J 8.2 Hz), 9.33 (1H, s), 9.59 (1H, s). MS (ES M+1) 416.

Intermediate XIV 2-Chloro-3-(1-fluoro-1-methylethyl)pyridine

To a solution of 2-(2-chloro-3-pyridinyl)propan-2-ol (1 g; 5.83 mmol) indichloromethane (10 mL) cooled to −70° C. was added diethylaminosulphurtrifluoride (1.1272 g; 0.857 mL; 6.993 mmol) dropwise. On completion ofthe addition the reaction mixture was allowed to warm to roomtemperature and stir for 30 min. TLC showed starting material consumed.The reaction mixture was poured onto sodium carbonate solution andextracted with dichloromethane. The dichloromethane extracts werecombined, washed with water, dried over magnesium sulphate filtered andevaporated under reduced pressure to give an oil. Yield=0.9 g. ¹H NMR(360 MHz) DMSO-d⁶ δ: 1.83 (3H, s), 1.89 (3H, s), 7.30 (1H, dd, J 4.6 and7.7 Hz), 8.00 (1H, dd, J 1.9 and 7.9 Hz), 8.34 (1 H, dd, J 1.9 and 4.7Hz).

Intermediate XV2-(3-Trifluoromethyl-2-pyridinyl)pyrido[2,3-d]pyridazin-5-one

A 3M solution of methylmagnesium iodide in ether (100 mL, 0.3 mol) wasadded to dry THF (300 mL) cooled in an ice bath. A solution of3-trifluoromethyl-2-pyridinecarbonitrile (41 g, 0.24 mol) in dry THF(100 mL) was then added under N₂, such that the internal temperature didnot exceed 10° C. When addition was complete (20 min) the mixture wasstirred at room temperature for 1 h. The mixture was then quenched witha saturated aqueous solution of ammonium chloride (100 mL) followed by2N HCl (200 mL). The product, 1-(3-trifluoromethyl-2-pyridinyl)ethanone,was extracted into ether (3×200 mL) and isolated as a brown oil (34 g).TLC: silica, EtAc:Hexane 1:3; Rf, 0.6. ¹H NMR (360 MHz) CDCl₃ δ: 2.62(3H, s), 7.45-7.49 (1H, m), 8.01 (1H, dd, J 0.8 and 8.1 Hz), 8.71 (1H,dd, J 0.8 and 8.1 Hz).

A mixture of the ethanone (2.8 g, 0.015 mol) and dimethylformamidedimethyl acetal (2.0 mL, 0.015 mol) was heated in a microwave apparatusat 160° C. for 10 min. This was repeated (×12) and the resulting darkoil was added to ethyl 3-aminocrotonate (40 g, 0.31 mol) in glacialacetic acid (500 mL) and heated conventionally at reflux for 18 h. Themixture was then concentrated and partitioned between diethyl ether(3×300 mL) and 2N NaOH solution (200 mL). The organic phase was washedwith brine (200 mL), dried MgSO₄) and concentrated to give a brown oilthat was purified by column chromatography on silica with EtAc:Hexane1:3→1:1 as eluant to give ethyl2-methyl-6-(3-trifluoromethyl-2-pyridinyl)pyridine-3-carboxylate as anoil (36 g). TLC: silica, EtAc:Hexane 1:1; Rf, 0.5. ¹H NMR (360 MHz)CDCl₃ δ: 1.43 (3H, t, J 7.2 Hz), 2.90 (3H, s), 4.42 (2H, q, J 7.2 Hz),7.48-7.51 (1H, m), 7.60 (1H, d, J 8.0), 8.13 (1H, dd, J 0.8 and 8.1 Hz),8.33 (1H, d, J 8.0 Hz), 8.85 (1H, d, J 8.1 Hz).

The ethyl carboxylate (36 g, 0.12 mol), N-bromosuccinimide (72 g, 0.4mol) and dibenzoyl peroxide (1 g) in carbon tetrachloride (700 mL) wereheated at reflux for 72 h and illuminated with a desk lamp. The mixturewas then filtered, and the mother liquor washed with 2M KOH solution(100 mL). The organic phase was dried (MgSO₄)and concentrated to give a1:9 mixture of mono- and dibromomethyl derivatives (50 g). This wasdissolved in ethanol (250 mL), hydrazine hydrate (25 mL) added and themixture heated at reflux for 18 h. The mixture was concentrated, theresidue triturated with water and Intermediate XV was collected byfiltration as a yellow solid (16 g). TLC: silica, EtAc; Rf, 0.5. ¹H NMR(400 MHz) DMSO-d⁶ δ: 7.80-7.85 (1H, m), 8.20 (1H, d, J 8.3 Hz), 8.41(1H, s), 8.44 (1 H, dd, J 1.1 and 8.0 Hz), 8.74 (1H, d, J 8.3 Hz), 8.01(1H, d, J 8.0 Hz).

Intermediate XVI2-(3-Trifluoromethyl-2-pyridinyl)pyrido[2,3-d]pyridazin-5-amine

Intermediate XV (0.4 g, 0.0014 mol) was heated in POCl₃ at reflux for 1h. The excess POCl₃ was then removed in vacuo and chased with toluene(×2). 150 mg of the residue was taken up in 33% aqueous ammonia (3 ml)and heated in a Smith microwave reactor for 30 min at 140° C. to giveIntermediate XVI ¹H NMR (400 MHz), DMSO-d⁶ δ: 8.83 (1H, dd, J 4.8, 0.8Hz), 8.77 (1H, d, J 0.4 Hz), 8.69 (1H, dd, J 8.4, 0.8 Hz), 8.27 (1H, dd,J 8.4, 1.6 Hz), 8.05 (1H, d, J, 8.4 Hz), 7.66-7.63 (1H, m), 7.21 (2H,s).

EXAMPLES Example 1N-(4-Trifluoromethylphenyl)-6-(3-trifluoromethyl-2-pyridinyl)-1-phthalazinamine

To Intermediate II (300.mg; 0.815 mmol), bis(pinacolato)diboron (227 mg;0.90 mmol), potassium acetate (159.96 mg; 1.63 mmol) and[1,1′bis(diphenylphosphino)ferrocene]palladium(II)chloride (29.81 mg;0.041 mmol) stirred under nitrogen for ten minutes was added 1,4-dioxane(10 mL). The reaction mixture was heated at reflux for 18 h. Afterallowing to cool, 2-chloro-3-trifluoromethylpyridine (148 mg; 0.8149mmol), 2M sodium carbonate solution (1 mL) and[1,1′bis(diphenylphosphino)ferrocene]palladium(II)chloride (29.81 mg;0.041 mmol) was added and the reaction mixture was heated at 100° C. for6 h. MS indicated product formation. The reaction mixture was filteredthrough celite and washed with ethyl acetate. The organic solution waswashed with brine, dried over magnesium sulphate, filtered andevaporated under reduced pressure to give an oil. The oil was purifiedon a silica column using a hexane/ethyl acetate gradient. Theappropriate fractions were combined and evaporated under reducedpressure to give a solid. The solid was tritiated with hexane andcollected by filtration to give the title compound Yield=135 mg (38%).¹H NMR (400 MHz) DMSO-d⁶ δ: 7.73 (1H, s), 7.75 (1H, s), 7.80 (1H, dd, J4.9 and 7.6), 8.13 (1H, d, J 8.6), 8.19-8.24 (3H, m), 8.44 (1H, dd, J1.2 and 8.2), 8.74 (1H, d, J 8.6), 9.01 (1H, d, J 4.3), 9.33 (1H, s),9.66 (1H, s); MS (ES M+1) 435.

Similarly prepared were:

Example 26-(3-Fluoro-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

¹H NMR (400 MHz) DMSO-d⁶ δ: 7.61-7.65 (1H, m), 7.73 (2H, d, J 8.6), 7.96(1 H, d, J 1.2), 7.99 (2 H, dd, J 1.4 and 3.3), 8.01 (1 H, d, J 1.2),8.23 (2 H, d, J 8.6) 8.56-8.58 (1H, m), 8.63 (1H, s), 8.67-8.69 (1 H,m), 8.75 (1H, s), 8.77 (1 H, s), 9.38 (1 H, s), 9.64 (1 H, s); MS (ESM+1) 385.

Example 3N-(4-(tert-Butylphenyl)-6-(3-trifluoromethyl-2-pyridinyl)-1-phthalazinamine

¹H NMR (360 MHz) DMSO-d⁶ δ: 1.32 (9H, s), 7.40 (2H, d, J 8.8), 7.79 (1H,dd, J 4.7 and 7.9), 7.84 (2H, d, J 8.4), 8.05-8.12 (2H, m), 8.42 (1H,dd, J 0.7 and 7.4), 8.69 (1H, d, J 8.8), 9.00 (1H, d, J 4.6), 9.18 (1H,s), 9.22 (1H, s); MS (ES M+1) 423.

Example 46-(3-Methyl-2-pyridinyl)-N-(4-(trifluoromethyl)phenyl)-1-phthalazinamine

To Intermediate II (300 mg; 0.815 mmol),3-methyl-2-(tributylstannyl)pyridine (467 mg; 1.22 mmol), lithiumchloride anhydrous (77.mg; 1.83 mmol) and copper(I)iodide (5.8 mg; 0.03mmol) in dioxane (3 mL) was addedtetrakis(triphenylphosphine)palladium(0) (35 mg; 0.03 mmol). Thereaction mixture was heated at 150° C. for 15 min in a Smith Microwavereactor. The catalyst was collected by filtration through a celite padand washed with ethyl acetate. The filtrate washed with brine, the ethylacetate extracts were combined, dried over magnesium sulphate, filteredand evaporated under reduced pressure to give an oil. The oil waspurified by flash chromatography using a gradient elution, hexane/ethylacetate (10:1) to ethyl acetate. The appropriate fractions were combinedand evaporated under reduced pressure to give a solid. The solid wasrecrystallized from acetonitrile, solid collected by filtration anddried. Yield=150 mg (48%). ¹H NMR (400 MHz) DMSO-d⁶ δ: 2.43 (3H, s),7.43 (1H, dd, J 4.7 and 7.8 Hz), 7.73 (2H, d, J 8.6 Hz), 7.84 (1H, dd, J1.0 and 7.6 Hz), 8.23-8.28 (4H, m), 8.59 (1H, dd, J 1.0 and 4.5 Hz),8.72 (1H, d, J 8.6 Hz), 9.31 (1H, s), 9.62 (1H, s); MS (ES M+1) 381.

Similarly prepared were:

Example 5 6-(3-Methyl-2-pyridinyl)-N-(4-trifluoromethoxyphenyl)-1-phthalazinamine

¹H NMR (400 MHz) DMSO-d⁶ δ: 2.43 (3H, s), 7.42-7.45 (3H, m), 7.86 (1H,dd, J 0.8 and 7.8 Hz), 8.00 (2H, d, J 9.0 Hz), 8.31-8.36 (2H, m), 8.61(1H, dd, J 0.8 and 4.7 Hz), 8.80 (1H, d, J 8.6 Hz), 9.31 (1H, s); MS (ESM+1) 397.

Example 6 6-(2-Pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

¹H NMR (400 MHz) DMSO-d⁶ δ: 7.58 (1H, dd, J 1.2 and 2.7), 7.88 (2H, d, J8.6), 8.03 (2H, d, J 8.6), 8.07-8.12 (1H, m), 8.33 (1H, d, J 8.2),8.84-8.85 (1H, m) 9.04 (1H, dd, J 2.0 and 8.6), 9.17 (2H, dd, J 1.6 and7.4), 9.70 (1H, s), 11.05-11.26 (1H, br s); MS (ES M+1) 367.

Example 7N-(4-Trifluoromethylphenyl)-2-(3-trifluoromethyl-2-pyridinyl)pyrido[2,3-d]pyridazin-5-amine

Intermediate XV (0.4 g, 0.0014 mol) was heated in POCl₃ at reflux for 1h. The excess POCl₃ was then removed in vacuo and chased with toluene(×2). The residue was dissolved in dioxane (10 mL),4-aminobenzotrifluoride (0.45 g, 0.0028 mol) added and the mixtureheated at reflux for 30 min. The mixture was concentrated and purifiedby chromatography on silica with EtOAc:Hexanes→EtOAc as eluent and theproduct recrystallised from ethanol to afford the title compound as anoff-white solid (50 mg). ¹H NMR (360 MHz), DMSO-d⁶ δ: 7.76 (2H, d, J 8.5Hz), 7.8-7.9 (1H, m), 8.23 (2H, d, J 8.5 Hz), 8.43 (1H, d, J 8.5 Hz),8.48 (1H, d, J, 8.5 Hz), 9.05 (1H, s), 9.29-9.24 (2H, m), 9.84 (1H, s).

Example 7aN-(4-Trifluoromethylphenyl)-2-(3-trifluoromethyl-2-pyridinyl)-pyrido[2,3-d]pyridazin-5-aminebenzenesulfonate salt

Example 7 was dissolved in DMF at room temperature and benzenesulfonicacid (1.2 eq) added. The solution was aged for 1 h, then slowly dilutedwith isopropyl acetate over 90 min. After aging for 4 h, the slurry wasfiltered and the cake was washed with isopropyl acetate. The yellowcrystalline solid was dried at room temperature in vacuum to constantweight. Yield 94%.

Example 7bN-(4-Trifluoromethylphenyl)-2-(3-trifluoromethyl-2-pyridinyl)pyrido[2,3-d]pyridazin-5-aminehydrochloride salt

Example 7 was dissolved in hot ethanol and a 2M solution of HCl in ether(excess) added. The suspension was aged for 1 h, the slurry was filteredand the cake was washed with ethanol and ether. The solid was dried atroom temperature in vacuum to constant weight. Yield 90%. ¹H NMR (360MHz) DMSO-d⁶ δ: 7.84 (2H, d, 8.6 Hz), 7.85-7.80 (1H, m), 8.11 (1H, dd, J8.4 Hz), 8.5 (2H, m), 9.05 (1H, d, J 3.8 Hz), 9.33 (1H, s), 9.49 (1H, J8.6 Hz).

Example 86-(1-Methyl-1H-imidazol-2-yl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

To a stirred solution of N-methylimidazole (97 μL, 1.23 mmol) intetrahydrofuran (2 mL) at −78° C. was added n-butyllithium (1.6 M inhexanes, 0.82 mL, 1.30 mmol) dropwise. The colorless solution wasstirred for 30 mins then zinc chloride (500 mg, 3.6 mmol) intetrahydrofuran (3 mL) was added via cannula. The reaction was allowedto warm to 0° C. over 1 h and then to room temperature over a furtherhour. Intermediate II (150 mg, 0.408 mmol) andtetrakis(triphenylphoshine)palladium (23 mg, 8.16 μmol) were dissolvedin tetrahydrofuran (2 ml) and added to the reaction mixture via cannula.Nitrogen was then bubbled through the mixture and it was then heated toreflux and stirred for 16 h. After cooling the reaction mixture waspoured into a solution of ethylenediaminetetraaceticacid disodium salt(11 g) in 100 mL water. The mixture was then basified by addition ofsolid sodium bicarbonate, extracted three times with ethyl acetate anddried over sodium sulfate. After filtration, the mixture waspre-adsorbed onto silica gel and purified by column chromatography (5%methanol in methylene chloride). ¹H NMR (400 MHz, DMSO-d⁶) δ: 9.60 (1H,s) 9.31 (1H, s), 8.69 (1H, d J 9.0 Hz), 8.42-8.40 (2H, m), 8.22 (2H, d,J 8.6 Hz), 7.72 (2H, d, J 8.6 Hz), 7.41 (1H, s), 7.11 (1H, s), 3.94 (3H,s); MS (MH⁺) 370.

Example 94-Methoxy-6-(3-methyl-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

Intermediate VII (100 mg, 0.25 mmol), anhydrous lithium chloride (31 mg,0.75 mmol), 3-methyl-2-tributylstannyl-pyridine (144 mg, 0.38 mmol), CuI(4.9 mg, 0.03 mmol.) and Pd(PPh₃)₄ (14.5 mg, 0.01 mmol) were suspendedin dioxane (3 mL) and irradiated with microwave radiation at 160° C. for15 min. The mixture was filtered and concentrated to give a dark brownoil, which was purified by flash chromatography (25→50% ethylacetate—isohexane) to give an off-white solid (24 mg, 23%). 1H NMR (500MHz, DMSO-d⁶) δ: 2.41 (3H, s), 4.13 (3H, s), 7.41 (1H, dd, J 4.5 and 7.5Hz), 7.67 (2H, d, J 8.4 Hz), 7.82 (1H, d, J 7.6 Hz), 8.13 (2H, d, J 8.7Hz), 8.26 (1H, dd, J 1.7 and 8.6 Hz), 8.29 (1H, s), 8.58 (1H, d, J 3.9Hz), 8.64 (1H, 8.6 Hz), 9.40 (1H, s); MS (ES M+1) 411.

Example 107-(3-Methyl-2-pyridinyl)-N-(4-trifluoromethylphenyl)pyrido[3,4-d]pyridazin-4-amine

Intermediate XII (83 mg, 0.35 mmol) was suspended in POCl₃ (5 mL) andheated to 100° C. for 5 h, and concentrated to dryness. The residue wassuspended in dioxane (4 ml), and methanol (4 mL) was added to solubilizethe mixture, which was then treated with the4-trifluoromethylphenylamine (0.217 ml, 1.74 mmol.) at 100° C.overnight. The residue was filtered, partitioned between NaHCO₃ (sat.aq.)/DCM, and the aqueous phase was extracted (DCM×2). The combinedorganic phases were dried (sodium sulfate) and concentrated to give abrown oily residue. Purification by flash chromatography (eluent:20→100% ethyl acetate/isohexane) gave on off-white solid, (10 mg, 7%)

¹H NMR (500 MHz, DMSO-d⁶) δ: 2.57 (3H, s), 7.46 (1H, dd, J 4.5 and 7.5Hz), 7.77 (2H, d, J 8.5 Hz), 7.84 (1H, d, J 8.5 Hz), 8.25 (2H, d, J 8.5Hz), 8.46 (1H, s), 8.60 (1H, d, J 4.0 Hz), 9.44 (1H, s), 9.96 (1H, s),10.07 (1H, s); MS (ES M+1) 382.

Example 114-Dimethylamino-6-(3-methylpyridin-2-yl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

Prepared as described in Example 4 from Intermediate IX. Purified byreversed phase HPLC; MS (ES M+1) 424.

Example 126-(3-Methylpyridin-2-yl)-4-(morpholin-4-yl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

Prepared as described in Example 4 from Intermediate X. Purified byreversed phase HPLC; MS (ES M+1) 466.

Example 136-(3-Methoxy-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

To Intermediate XIII (250 mg; 0.60 mmol) and 2-chloro-3-methoxypyridine(95 mg; 0.66 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)chloride (22 mg; 0.030 mmol) in 1,4-dioxane (4 mL) wasadded sodium carbonate solution (1 mL). The reaction mixture was heatedat 150° C. for 15 min in a Smith microwave reactor. The reaction mixturewas poured into water and extracted with ethyl acetate. The ethylacetate extracts were combined, washed with brine, dried over magnesiumsulphate, filtered and evaporated under reduced pressure. The residuewas purified by flash chromatography using ethyl acetate as eluant. Theappropriate fractions were combined and evaporated under reducedpressure to give a solid. The solid was recrystallized fromacetonitrile, collected by filtration and dried to give the titlecompound. Yield=55 mg (23%). ¹H NMR (500 MHz, DMSO-d⁶) δ: 3.96 (3H, s),7.51 (1H, m), 7.71 (1H, d, J 8.8 Hz), 7.73 (2H d J 8.6 Hz) 8.24 (2H, d,J 8.6 Hz) 8.38 (1H, dd J 4.6 and 1.0 Hz), 8.5 (1H, d, 8.4) 8.62 (1H, s),8.67 (1H, d, J 8.8) 9.33 (1H, s), 9.60 (1H, s); MS (ES M+1) 397.

Similarly prepared were:

Example 142-{2-[1-(4-Trifluoromethylphenylamino)phthalazin-6-yl]pyridin-3-yl}propan-2-ol

¹H NMR (500 MHz, DMSO-d⁶) δ: 1.33 (6H, s), 2.07 (1H, s), 5.00 (1H, s),7.48 (1H, dd, J 4.6 and 8.1 Hz), 7.73 (2H, d, J 8.6 Hz), 8.00 (1H, s),8.01 (1H, s), 8.16 (1H, dd, J 1.3 and 8.2 Hz), 8.24 (2H, d, J 8.6 Hz),8.52 (1H, dd, J 1.1 and 4.5 Hz), 8.61 (1H, d, J 9.0 Hz), 9.26 (1H, s),9.58 (1H, s); MS (ES M+1) 425.

Example 15N-(4-Trifluoromethylphenyl)-6-(5-trifluoromethyl-2-pyridinyl)-1-phthalazinamine

¹H NMR (400 MHz, DMSO-d⁶) δ: 7.73 (2H, d, J 8.6 Hz), 8.23 (2H, d, J 8.6Hz), 8.43-8.50 (2H, m), 8.78 (2H, dd, J 2.3 and 1.6 Hz), 8.90 (1H, s),9.17 (1H, d, J 1.2 Hz), 9.36 (1H, s), 9.63 (1H, s); MS (ES M+1) 435.

Example 16N-(4-Trifluoromethylphenyl)-6-(6-trifluoromethyl-2-pyridinyl)-1-phthalazinamine

¹H NMR (400 MHz, DMSO-d⁶) δ: 7.74 (2H, d, J 8.6 Hz), 8.02 (1H, d, J 7.4Hz), 8.23 (2H, d, J 8.6 Hz), 8.33 (1H, t, J 7.8 Hz), 8.58 (1H, d, J 7.8Hz), 8.73-8.79 (2H, m), 8.84 (1H, d, J 1.2 Hz), 9.39 (1H, s), 9.65 (1H,s); MS (ES M+1) 435.

Example 17N-(4-Trifluoromethylphenyl)-6-(4-trifluoromethyl-2-pyridinyl)-1-phthalazinamine

¹H NMR (400 MHz, DMSO-d⁶) δ: 7.73 (2H, d, J 8.6 Hz), 7.90 (1H, dd, J 0.8and 5.1 Hz), 8.24 (2H, d, J 8.2 Hz), 8.62 (1H, s), 8.78 (1H, s),8.84-8.86 (1H, m), 8.96 (1H, d, J 1.6 Hz), 9.07 (1H, d, J 5.1 Hz), 9.35(1H, s), 9.65 (1H, s); MS (ES M+1) 435.

Example 186-(4-Methyl-3-pyridazinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

¹H NMR (500 MHz, DMSO-d⁶) δ: 2.43 (3H, s), 7.73-7.77 (3H, n), 8.25 (2H,d, J 8.6 Hz) 8.32 (1H, n), 8.39 (1H, s), 8.78 (1H, d, J 8.8 Hz), 9.18(1H, d, J 5.1 Hz), 9.34 (1H, s), 9.66 (1H, s).

Example 196-(5-Methyl-4-pyrimidinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

¹H NMR (500 MHz, DMSO-d⁶) δ: 2.61 (3H, s), 7.73 (2H, d, J 8.6 Hz), 8.23(2H, d, J 8.3 Hz), 8.28 (1H, s), 8.79 (2H, s), 8.94 (1H, s), 9.23 (1H,s), 9.36 (1H, s) 9.65 (1H, s).

Example 206-(3-Methyl-2-pyrazinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

¹H NMR (500 MHz, DMSO-d⁶) δ: 2.67 (3H,s), 7.73 (2H, d, J 8.8Hz), 8.23(2H, d, J 8.6 Hz), 8.32 (1H, m), 8.39 (1H, s), 8.65 (2H, m), 8.75 (1H,d, J 8.6Hz), 9.33 (1H, s), 9.64 (1H, s).

Example 21N-(4-Trifluoromethylphenyl)-6-(4-trifluoromethyl-3-pyridazinyl)-1-phthalazinamine

¹H NMR (500 MHz, DMSO-d⁶) δ: 7.66 (2H, d, J 8.6 Hz), 8.1 (2H, d, J 8.6Hz), 8.21 (1H, d, J 8.6 Hz), 8.24 (1H, d, J 5.4 Hz), 8.29 (1H, s), 8.66(1H, d, J 8.6 Hz), 9.22 (1H, s), 9.61 (1H, d, J 5.5 Hz).

Example 22N-(4-tert-Butylphenyl)-6-(3-methyl-2-pyridinyl)-1-phthalazinaminehydrochloride

1-Chloro-6-(3-methyl-2-pyridinyl)phthalazine (200 mg; 0.78 mmol) and4-tert-butylaniline (117 mg, 0.125 mL; 0.78 mmol) in 1,4-dioxane wereheated at reflux for 2 h. After allowing to cool down to roomtemperature the precipitate was collected by filtration washed with1,4-dioxane and dried to give the title compound (135 mg) (43%). ¹H NMR(500 MHz, DMSO-d⁶) δ: 1.35 (9H, s), 7.48 (1H, dd, J 4.9 and 7.6 Hz),7.55-7.61 (4H, m), 7.90 (1H, dd, J 0.8 and 7.8 Hz), 8.47 (1H, dd, J 1.6and 8.6 Hz), 8.52 (1H, d, J 2.0 Hz), 8.63 (1H, dd, J 1.2 and 4.7 Hz),9.09 (1H, d, J 8.6), 9.32 (1H, s); MS (ES M+1) 369.

Similarly prepared was:

Example 23 N-(4-Fluorophenyl)-6-(3-methyl-2-pyridinyl)-1-phthalazinamine

¹H NMR (500 MHz, DMSO-d⁶) δ: 2.42 (3H, s), 7.22 (2H, t, J 8.8), 7.42(1H, dd, J 4.7 and 7.4), 7.83 (1H, d, J 7.8), 7.98 (2H, dd, J 5.1 and8.2), 8.19-8.22 (2H, m), 8.58 (1H, d, J 3.9), 8.66 (1H, d, J 8.6), 9.20(1H, s), 9.28 (1H, s).

Example 246-(2-Methoxyphenyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

Intermediate II (200 mg; 0.54 mmol), 2-methoxyphenylboronic acid (123.8mg; 0.814 mmol) and1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride (0.0199 g;0.027 mmol) was added sodium carbonate solution (1 mL) and 1,4-dioxane(4 mL). The reaction mixture was heated in a Smith microwave reactor for15 min at 150° C. to product MS (ES M+1) 396. The reaction mixture waspoured into water and extracted with dichloromethane. Thedichloromethane extracts were combined, dried over magnesium sulphate,filtered and evaporated under reduced pressure to give an oil. The oilwas purified by flash chromatography using gradient elution (90→50%)iso-hexane/ethyl acetate (1:1). The appropriate fractions were combinedand evaporated under reduced pressure to give a solid. The solid wasrecrystallized from acetonitrile, collected by filtration and dried togive the title compound (0.095 g; 44%). ¹H NMR (400 MHz, DMSO-d⁶) δ:3.83 (3H, s), 7.11-7.15 (1H, m), 7.22 (1H, d, J 8.2 Hz), 7.45-7.51 (2H,m), 7.72 (2H, d, J 8.6 Hz), 8.17 (1H, s), 8.23 (2H, d, J 8.2 Hz), 8.63(1 H, d, J 8.6), 9.26 (1H, s), 9.56 (1 H, s); MS (ES M+1) 396.

Example 256-(2-Cyanophenyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

The title compound was prepared from2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzonitrile andIntermediate II using the procedure described in Example 24. ¹H NMR (400MHz, DMSO-d⁶) δ: 7.69-7.75 (3H, m,), 7.83 (1H, d, J 7.0 Hz), 7.91 (1H,m), 8.08 (1H, dd, J 0.8 and 7.8 Hz), 8.24 (1H, d, J 8.6 Hz), 8.27 (1H,dd, J 1.95 and 8.6 Hz), 8.32 (1H d, J 1.2 Hz) 8.78 (1H, d, J 8.6 Hz),9.33 (1H, s), 9.66 (1H, s); MS (ES M+1) 391.

Example 263-(3-Methylpyridin-2-yl)-N-(4-trifluoromethylphenyl)pyrido[2,3-d]pyridazin-8-amine

To a solution of ethyl 5-bromo-3-methylpyridine-2-carboxylate (1.6 g;6.95 mmol) and benzoyl peroxide (84.23 mg; 0.347 mmol) in carbontetrachloride (20 mL) was added N-bromosuccinimide (2.47 g; 13.91 mmol).The reaction mixture was heated at reflux for 3 h. Another equivalent ofN-bromosuccinimide and benzoyl peroxide (85 mg) was added and refluxingwas continued for a further 7 h. Reaction was monitored by MS. After 10h the product was the major peak. The reaction mixture was allowed tocool, filtered through celite washed with carbon tetrachloride. Thefiltrate was evaporated under reduced pressure to give an oil, 2.7 g.The oil (2.7 g; 6.9615 mmol) and hydrazine hydrate (2.4 mL) in ethanolwas heated at reflux overnight. The solvent was evaporated under reducedpressure, the residue was taken-up in water acidified with 2N HCl thesolid obtained was collected by filtration washed with water and driedby azeotroping with toluene. Yield=0.9 g. The crude product andphosphorus oxychloride were heated at 60° C. for 1 h. The excessphosphorus oxychloride was evaporated under reduced pressure to give3-bromo-8-chloropyrido[2,3-d]pyridazine (0.97 g) as solid. This materialwas azeotroped with toluene and then treated with4-aminobenzotrifluoride (0.64 g, 0.495 mL; 3.97 mmol) in 1,4-dioxane(20ml) and heated at 40° C. for 1 h. The solvent was evaporated underreduced pressure and the residue partitioned between ethyl acetate andsodium carbonate solution. The ethyl acetate extracts were combined,washed with brine, dried over magnesium sulphate, filtered andevaporated under reduced pressure to give an oil. The oil was purifiedby flash chromatography using a gradient of (90→50%) iso-hexane/ethylacetate. The appropriate fractions were combined and evaporated underreduced pressure to give3-bromo-N-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-amine (100mg). ¹H NMR (500 MHz, DMSO-d⁶) δ: 7.73 (2H, d, J 8.6 Hz), 8.41 (2H, d, J8.8 Hz), 8.91 (1H, d, J 2.2 Hz), 9.25 (1H, s), 9.33 (1H, d, J 2.2 Hz),10.05 (1H, s).

The amine was reacted as in Example 4 to give the title compound. ¹H NMR(500 MHz, DMSO-d⁶) δ: 2.49 (3H, s), 7.49 (1H, dd, J 4.8 and 7.7 Hz),7.76 (2H, d, J 8.6 Hz), 7.90 (1H, dd, J 0.5 and 7.1 Hz), 8.47 (2H, d, J8.6 Hz), 8.66 (1H, dd, J 0.5 and 4.2 Hz), 8.80 (1H, d, J 2.0 Hz), 9.39(1H, s), 9.48 (1H, d, J 2.0 Hz), 10.10 (1H, s); MS (ES M+1) 382.

Following procedures described above the following compounds wereprepared:

Example 27N-(4-Ethoxycarbonylphenyl)-6-(3-methyl-2-pyridinyl)-1-phthalazinamine

¹H NMR (500 MHz, DMSO-d⁶) δ: 1.34 (3H, t, J 7.1 Hz), 2.43 (3H, s), 4.33(2H, q, J 7.1 Hz), 7.42 (1H, dd, J 4.8 and 7.7 Hz), 7.84 (1H, dd, J 0.7and 7.6 Hz), 7.98 (2H, d, J 8.8 Hz), 8.17 (2H, d, J 8.8 Hz), 8.24 (1H,dd, J 1.5 and 8.3 Hz), 8.28 (1 H, s), 8.59 (1H, dd, J 1.1 and 4.8 Hz),8.72 (1H, d, J 8.8 Hz), 9.32 (1H, s), 9.63 (1H, s).

Example 286-(3,5-Difluoro-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

¹H NMR (500 MHz, DMSO-d⁶) δ: 7.73 (2H, d, J 8.6 Hz), 8.20-8.25 (3H, m),8.52 (1H, d, J 8.6 Hz), 8.59 (1H, s), 8.76 (2H, dd, J 6.7 and 2.0 Hz),9.38 (1H, s), 9.64 (1H, s).

Example 296-(3-Cyano-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

¹H NMR (400 MHz, DMSO-d⁶) δ: 7.73-7.77 (3H, m), 8.24 (2H, d, J 8.2 Hz),8.50 (1H, dd, J 1.8 and 8.8 Hz), 8.55-8.59 (2H, m), 8.81 (1H, d, J 8.6Hz), 9.06 (1H, dd, J 1.8 and 4.9 Hz), 9.38 (1H, s), 9.69 (1H, s).

Example 306-(3-Ethoxycarbonyl-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

¹H NMR (500 MHz, DMSO-d⁶) δ: 0.98 (3H, t, J 7.1 Hz), 4.15 (2H, q, J 7.1Hz), 7.67 (1H, dd, J 4.9 and 7.8 Hz), 7.73 (2H, d, J 8.8 Hz), 8.16 (1H,dd, J 2.0 and 8.6 Hz), 8.21-8.25 (3H, m), 8.33 (1H, dd, J 1.7 and 7.8Hz), 8.69 (1H, d, J 8.6 Hz), 8.92 (1H, dd, J 1.6 and 4.8 Hz), 9.33 (1H,s), 9.63 (1 H, s).

Example 316-(3-(1-fluoro-1-methylethyl)-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine

¹H NMR (500 MHz, DMSO-d⁶) δ: 1.58 (3H, s), 1.62 (3H, s), 7.54-7.57 (1H,m), 7.73 (2H, d, J 8.6 Hz), 8.01-8.04 (3H, m), 8.23 (2H, d, J 8.6 Hz),8.64 (2H, dd, J 1.6 and 4.8 Hz), 9.27 (1 H, s), 9.60 (1 H, s).

Example 32N-(4-Trifluoromethylphenyl)-2-(3-chloro-2-pyridinyl)pyrido[2,3-d]pyridazin-5-amine

¹H NMR (400 MHz), CDCl₃ δ: 7.08-7.18 (1H, m), 7.38-7.43 (1H, m), 7.68(2H, d, J 6.3 Hz), 7.92 (2H, d, J 6.6 Hz), 8.06-8.21 (1H, m), 8.70 (1H,d, J 3 Hz), 8.78-8.88 (1H, m), 8.94-9.01 (1H, m).

Example 33N-(5-Trifluoromethyl-2-pyridinyl)-2-(3-trifluoromethyl-2-pyridinyl)pyrido[2,3-d]pyridazin-5-amine

Intermediate XVI (56.9 mg, 1.96×10⁻⁴ mol) was dissolved in dioxane (4ml) and 2-bromo-5-trifluoromethylpyridine (44 mg, 196 μmol), caesiumcarbonate (90 mg), Xantphos (6.3 mg) andtris(dibenzylideneacetone)dipalladium(0) (4.2 mg) were added. Thereaction was degassed (by bubbling with N₂) and heated to reflux. Afterstirring for 16 h the reaction was allowed to cool to room temperatureand filtered through celite (washing with ethyl acetate). The reactionwas then quenched with saturated sodium bicarbonate, extracted threetimes with ethyl acetate, dried over sodium sulfate, filtered andconcentrated. Column chromatography (30% ethyl acetate in hexanes) wasfollowed by trituration from methanol to give the product (63 mg, 73%)¹H NMR (400 MHz), DMSO-d⁶ δ: 7.93-7.91 (1H, m), 8.24 (1H, dd, J 8.4, 2.4Hz), 8.39 (1H, d, J 8.4 Hz), 8.42 (1H, d, J 8.1 Hz), 8.55 (1H, dd, J8.0, 1.2 Hz), 8.60 (1H, d, J 8.1 Hz), 8.85 (1H, s), 9.0 (1H, s), 9.10(1H, dd, J 4.4, 0.8 Hz), 9.23 (1H, d, J 8.8 Hz).

1. A compound of formula (I):

wherein Ar is phenyl, a six-membered heteroaromatic group containingone, two or three nitrogen atoms or a five-membered heteroaromatic groupcontaining one, two, three or four heteroatoms chosen from oxygen,nitrogen and sulfur, at most one heteroatom being oxygen or sulfur, Arbeing optionally substituted with one, two or three groups independentlychosen from halogen, hydroxy, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₂₋₆alkenyloxy, C₂₋₆alkynyloxy, amino, haloC₁₋₆alkyl,haloC₂₋₆alkenyl, haloC₂₋₆alkynyl, hydroxyC₁₋₆alkyl, hydroxyC₂₋₆alkenyl,hydroxyC₂₋₆alkynyl, cyano, nitro, aminoC₁₋₆alkyl, aminoC₂₋₆alkenyl,aminoC₂₋₆alkynyl, C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆alkylthio,C₁₋₆alkoxycarbonyl, haloC₁₋₆alkoxy, haloC₂₋₆alkenyloxy,haloC₂₋₆alkynyloxy, NR⁴R⁵, CONR⁴R⁵ or CO₂NR⁴R⁵ where each R⁴ and R⁵ isindependently hydrogen or C₁₋₆alkyl; R¹ is phenyl, a six-memberedheteroaromatic group containing one, two or three nitrogen atoms or afive-membered heteroaromatic group containing one, two, three or fourheteroatoms chosen from oxygen, nitrogen and sulfur, at most oneheteroatom being oxygen or sulfur, Ar being optionally substituted withone, two or three groups independently chosen from halogen, hydroxy,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₂₋₆alkenyloxy,C₂₋₆alkynyloxy, amino, haloC₁₋₆alkyl, haloC₂₋₆alkenyl, haloC₂₋₆alkynyl,hydroxyC₁₋₆alkyl, hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl, cyano, nitro,aminoC₁₋₆alkyl, aminoC₂₋₆alkenyl, aminoC₂₋₆alkynyl, C₁₋₆alkylsulfonyl,C₁₋₆alkylsulfinyl, C₁₋₆alkylthio, C₁₋₆alkoxycarbonyl, haloC₁₋₆alkoxy,haloC₂₋₆alkenyloxy, haloC₂₋₆alkynyloxy, NR⁴R⁵, CONR⁴R⁵ or CO₂NR⁴R⁵ whereR⁴ and R⁵ are as defined above; R² is hydrogen, halogen, hydroxy,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₂₋₆alkenyloxy,C₂₋₆alkynyloxy, NR⁶R⁷ where R⁶ and R⁷ are, independently, hydrogen,C₁₋₆alkyl or C₁₋₆hydroxyalkyl, or R⁶ and R⁷, together with the nitrogenatom to which they are attached form a 4, 5 or 6-membered stableheterocycle optionally containing an oxygen ring atom; R³ is hydrogen orC₁₋₆alkyl; each X, Y and Z is N or CR⁸ where R⁸ is hydrogen, halogen orC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 2. A compoundaccording to claim 1 in which Z is N and X and Y are CH.
 3. A compoundaccording to claim 1 or 2 in which R¹ is para-substituted phenyl orpyridyl.
 4. A compound according to claim 1, 2 or 3 in which Ar ispyridyl monosubstituted at the ring position adjacent to the point ofattachment of Ar to the rest of the molecule.
 5. A compound according toany preceding claim in which R² is hydrogen, dimethylamino ormorpholino.
 6. A compound according to claim 1 which is:N-(4-trifluoromethylphenyl)-6-(3-trifluoromethyl-2-pyridinyl)-1-phthalazinamine;6-(3-fluoro-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;N-(4-(tert-butylphenyl)-6-(3-trifluoromethyl-2-pyridinyl)-1-phthalazinamine;6-(3-methyl-2-pyridinyl)-N-(4-(trifluoromethylphenyl)-1-phthalazinamine;6-(3-methyl-2-pyridinyl)-N-(4-trifluoromethoxyphenyl)-1-phthalazinamine;6-(2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;N-(4-trifluoromethylphenyl)-2-(3-trifluoromethyl-2-pyridinyl)pyrido[2,3-d]pyridazin-5-amine;6-(1-methyl-1H-imidazol-2-yl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;4-methoxy-6-(3-methyl-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;7-(3-methyl-2-pyridinyl)-N-(4-trifluoromethylphenyl)pyrido[3,4-d]pyridazin-4-amine;4-dimethylamino-6-(3-methylpyridin-2-yl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;6-(3-methylpyridin-2-yl)-4-(morpholin-4-yl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;6-(3-methoxy-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;2-{2-[1-(4-trifluoromethylphenylamino)phthalazin-6-yl]1pyridin-3-yl}propan-2-ol;N-(4-trifluoromethylphenyl)-6-(5-trifluoromethyl-2-pyridinyl)-1-phthalazinamine;N-(4-trifluoromethylphenyl)-6-(6-trifluoromethyl-2-pyridinyl)-1-phthalazinamine;N-(4-trifluoromethylphenyl)-6-(4-trifluoromethyl-2-pyridinyl)-1-phthalazinamine;6-(4-methyl-3-pyridazinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;6-(5-methyl-4-pyrimidinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;6-(3-methyl-2-pyrazinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;N-(4-trifluoromethylphenyl)-6-(4-trifluoromethyl-3-pyridazinyl)-1-phthalazinamine;N-(4-tert-butylphenyl)-6-(3-methyl-2-pyridinyl)-1-phthalazinaminehydrochloride;N-(4-fluorophenyl)-6-(3-methyl-2-pyridinyl)-1-phthalazinamine;6-(2-methoxyphenyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;6-(2-cyanophenyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;3-(3-methylpyridin-2-yl)-N-(4-trifluoromethylphenyl)pyrido[2,3-d]pyridazin-8-amine;N-(4-ethoxycarbonylphenyl)-6-(3-methyl-2-pyridinyl)-1-phthalazinamine;6-(3,5-difluoro-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;6-(3-cyano-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;6-(3-ethoxycarbonyl-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;6-(3-(1-fluoro-1-methylethyl)-2-pyridinyl)-N-(4-trifluoromethylphenyl)-1-phthalazinamine;N-(4-trifluoromethylphenyl)-2-(3-chloro-2-pyridinyl)pyrido[2,3-d]pyridazin-5-amine;andN-(5-trifluoromethyl-2-pyridinyl)-2-(3-trifluoromethyl-2-pyridinyl)pyrido[2,3-d]pyridazin-5-amine;or a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising a compound according to any one of claims 1 to 6or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient.
 8. A compound according to any one of claims 1 to6 or a pharmaceutically acceptable salt thereof for use in a method oftreatment of the human or animal body by therapy.
 9. Use of a compoundaccording to any one of claims 1 to 6 or a pharmaceutically acceptablesalt thereof for the manufacture of a medicament for treating orpreventing pain and/or inflammation.
 10. A method of treating orpreventing pain and/or inflammation in a subject suffering from or proneto pain and/or inflammation which comprises administering to thatsubject a therapeutically effective amount of a compound according toclaim 1 or a pharmaceutically acceptable salt thereof.